The Rationale Behind Combination Therapy in mRCC

David F. McDermott, MD: When you think about it, I think kidney cancer is traditionally a very VEGF-driven tumor. The story goes back to the VHL [Von Hippel-Lindau] mutation, which is common in about 70% of patients with clear-cell kidney cancer, which is the predominant cell type for patients with advanced disease. Patients with a VHL mutation are often overexpressing hypoxia-inducible factor, or HIF. This leads to the production of a variety of proteins, including VEGF, which make these tumors very vascular. Traditionally, that has made them resistant to things like chemotherapy and radiation, but more sensitive than most other solid tumors to targeted therapies that go after VEGF signaling in one way or the other. That biology is common, and that’s where anti-VEGF strategies have a role.

We’ve also know for a long time that kidney cancer is a rather immune-responsive solid tumor, where you could actually see in some patients a lot of infiltration of their tumor with immune cells at presentation and you could also see spontaneous remissions in rare cases after surgery, which may be through an immune mechanism. Those insights led to the development of the first cytokine-based immune therapies, which produced dramatic benefits but also significant toxicities. But the benefits were only in a small number of patients.

Now, with this immune checkpoint blockade story, we’re actually making much bigger gains on the immune therapy side. We’re actually able to take these immune cells that are already at the tumor, but not killing it, and unleash them to actually produce significant benefits in a subset of patients.

Brian Rini, MD: Combination therapy is becoming the cornerstone of kidney cancer therapy, much like other solid tumors where the paradigm for cure has been—say, in testicular cancer—multiagent chemotherapy and not single-agent chemotherapy. In cancer, we’re moving [toward] the time of not just monotherapy, which is unlikely to cure, but some of these checkpoint-based combinations. Especially combinations of immune agents have the potential to cure. Therefore, I think we’re willing to put up with a little more toxicity from combinations to achieve cure in a fraction of patients.

I don’t think all patients need combination therapy. It’s a great question, because there are probably patients who can get away with monotherapy. I certainly have patients in my clinic who had been on trials of monotherapy who are doing well many years later. Some of them are in CR [complete remission] or near CR. We don’t know. We haven’t done the trials yet. We jumped in with combinations in these phase III trials, which are turning out to be very active. Now we’re going to go back and test monotherapy in a subset of patients. Like anything, there will be patients who need more intense therapy and patients who can get away with less, and obviously we should give them the least intensive therapy that gives them the best outcome. I don’t think all patients need combination therapy, no.

David F. McDermott, MD: I worry that with all these exciting new data over the last year with combination approaches, we might get to the point where we’re applying them in a blanket way and not specifically for one patient or the other. We can still see dramatic benefits with single-agent therapy, both VEGF and immune-checkpoint blockade, in trials. There may be some patients who only need single agents in the beginning. There may be patients who benefit from a VEGF plus PD-1 inhibitor and others who need a PD-1 inhibitor plus CTLA4 strategy. We need to figure out who those patients are because there are going to be significant costs associated with combinations and more toxicity associated with combinations. It may be that not every patient needs that approach right from the beginning.

Transcript Edited for Clarity

Transcript:

David F. McDermott, MD: When you think about it, I think kidney cancer is traditionally a very VEGF-driven tumor. The story goes back to the VHL [Von Hippel-Lindau] mutation, which is common in about 70% of patients with clear-cell kidney cancer, which is the predominant cell type for patients with advanced disease. Patients with a VHL mutation are often overexpressing hypoxia-inducible factor, or HIF. This leads to the production of a variety of proteins, including VEGF, which make these tumors very vascular. Traditionally, that has made them resistant to things like chemotherapy and radiation, but more sensitive than most other solid tumors to targeted therapies that go after VEGF signaling in one way or the other. That biology is common, and that’s where anti-VEGF strategies have a role.

We’ve also know for a long time that kidney cancer is a rather immune-responsive solid tumor, where you could actually see in some patients a lot of infiltration of their tumor with immune cells at presentation and you could also see spontaneous remissions in rare cases after surgery, which may be through an immune mechanism. Those insights led to the development of the first cytokine-based immune therapies, which produced dramatic benefits but also significant toxicities. But the benefits were only in a small number of patients.

Now, with this immune checkpoint blockade story, we’re actually making much bigger gains on the immune therapy side. We’re actually able to take these immune cells that are already at the tumor, but not killing it, and unleash them to actually produce significant benefits in a subset of patients.

Brian Rini, MD: Combination therapy is becoming the cornerstone of kidney cancer therapy, much like other solid tumors where the paradigm for cure has been—say, in testicular cancer—multiagent chemotherapy and not single-agent chemotherapy. In cancer, we’re moving [toward] the time of not just monotherapy, which is unlikely to cure, but some of these checkpoint-based combinations. Especially combinations of immune agents have the potential to cure. Therefore, I think we’re willing to put up with a little more toxicity from combinations to achieve cure in a fraction of patients.

I don’t think all patients need combination therapy. It’s a great question, because there are probably patients who can get away with monotherapy. I certainly have patients in my clinic who had been on trials of monotherapy who are doing well many years later. Some of them are in CR [complete remission] or near CR. We don’t know. We haven’t done the trials yet. We jumped in with combinations in these phase III trials, which are turning out to be very active. Now we’re going to go back and test monotherapy in a subset of patients. Like anything, there will be patients who need more intense therapy and patients who can get away with less, and obviously we should give them the least intensive therapy that gives them the best outcome. I don’t think all patients need combination therapy, no.

David F. McDermott, MD: I worry that with all these exciting new data over the last year with combination approaches, we might get to the point where we’re applying them in a blanket way and not specifically for one patient or the other. We can still see dramatic benefits with single-agent therapy, both VEGF and immune-checkpoint blockade, in trials. There may be some patients who only need single agents in the beginning. There may be patients who benefit from a VEGF plus PD-1 inhibitor and others who need a PD-1 inhibitor plus CTLA4 strategy. We need to figure out who those patients are because there are going to be significant costs associated with combinations and more toxicity associated with combinations. It may be that not every patient needs that approach right from the beginning.